PB1884: ENGAGING INNATE IMMUNITY: A PHASE 1 DOSE ESCALATION STUDY TO ASSESS SAFETY AND TOLERABILITY OF AFM28 MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY CD123-POSITIVE ACUTE MYELOID LEUKEMIA (AML)
Authors: Montserrat Arnan, Pau Montesinos, Stéphane de Botton, Christian Recher, Lydia Wunderle, Michael Emig, Andreas Harstrick, Kerstin Pietzko, Sheena Pinto, Paulien Ravenstijn, Naval Daver
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: AML is an aggressive malignancy of the bone marrow characterised by uncontrolled proliferation of undifferentiated myeloid cells, originating from leukemic stem cells (LSCs). Prognosis in patients with AML is poor, particularly in the relapsed or refractory (R/R) setting, where no effective standard-of-care regimens are available for patients without targetable FLT3 or IDH mutations. As relapse may in some cases be driven by a population of LSCs resistant to prior therapy, treatments that target both leukemic blasts and LSCs would likely optimally prevent relapse. The human interleukin-3 receptor alpha subunit (CD123) is a promising target due to its almost universal expression, and differential overexpression, on leukemic blasts and LSCs, but limited expression in healthy blood cells and healthy stem/progenitors. The Innate Cell Engager (ICE®) AFM28, is a bispecific monoclonal antibody with specificity for CD123 and the human Fc gamma receptor III-A (CD16A). AFM28 is intended to be developed as an antineoplastic agent for haematological malignancies known to express CD123, including AML. Its primary pharmacological mechanism of action is the induction of antibody-dependent cellular cytotoxicity (ADCC) by CD16A-expressing immune effector cells, primarily natural killer (NK) cells, towards CD123-expressing cells. In preclinical studies, AFM28 potently induced NK cell-mediated anti-leukemic activity, including depletion of LSCs. ADCC was also activated irrespective of AML mutational status and CD64 expression and, importantly, even at low levels of CD123 expression. In non-human primates, AFM28 exhibited the anticipated pharmacodynamic (PD) activity and was well-tolerated with only low levels of cytokine release and no sign of cytokine-related toxicities. These findings support clinical investigation of AFM28 in patients with AML and suggest the potential to combine AFM28 with other therapies, in particular adoptive, allogeneic NK cell therapy. Aims: This first-in-human study aims to investigate the safety and tolerability of AFM28 monotherapy, establish the maximum tolerated dose (MTD), determine the recommended Phase 2 dose (RP2D), and establish the potential for this novel treatment modalities to redirect NK cells to eliminate leukemic blasts and LSCs thereby potentially achieving durable remissions in patients with R/R AML. Methods: AFM28-101 (EudraCT number: 2022-002702-24) is a phase 1, open-label, non-randomised, multicentre, multiple ascending dose escalation study evaluating AFM28 monotherapy in patients with CD123-positive R/R AML; the planned study design is shown in Figure 1. Patients will receive AFM28 intravenously once weekly until disease progression or other treatment discontinuation criteria are met, intolerable toxicity, patient withdrawal, or termination at the investigator’s discretion. The dose escalation will be guided by an adaptive 2-parameter Bayesian logistic regression model to evaluate AFM28. The primary endpoint will be assessed by the incidence of dose limiting toxicities considering the totality of treatment-emergent adverse events (TEAEs, evaluated using among others Common Terminology Criteria for Adverse Events [CTCAE, v5.0]). Secondary endpoints include the incidence and severity of TEAEs, immunogenicity characterised by the incidence of subjects developing antibody-drug antibodies and characterising pharmacokinetics. The preliminary anti leukemic and PD activity of AFM28 will also be assessed. The totality of the data emerging from this study will be considered in the RP2Ds selection for further development. Results: N/A Summary/Conclusion: N/AKeywords: ADCC, Acute myeloid leukemia, NK cell, Immune therapy